Clinical and electrophysiological features of <i>SCN8A</i> variants causing episodic or chronic ataxia
Notice bibliographique
Résumé
Abstract Objective Variants in SCN8A are associated with a spectrum of epilepsies and neurodevelopmental disorders. Ataxia as a predominant symptom of SCN8A variation has not been well studied. We set out to investigate disease mechanisms and genotype-phenotype correlations of SCN8A -related ataxia. Methods We collected genetic and electro-clinical data of ten individuals from nine unrelated families carrying novel SCN8A variants associated with chronic progressive or episodic ataxia. Electrophysiological characterizations of these variants were performed in ND7/23 cells and cultured neurons. Results Variants associated with chronic progressive ataxia either significantly decreased Na + current densities and shifted activation curves towards more depolarized potentials (p.Asn995Asp, p.Lys1498Glu and p.Trp1266Cys) or resulted in a premature stop codon (p.Trp937Ter), i.e. strong loss-of-function (LOF) effects. Three variants (p.Arg847Gln and biallelic p.Arg191Trp/p.Asp1525Tyr) were associated with episodic ataxia causing LOF by decreasing Na + current densities or a hyperpolarizing shift of the inactivation curve. Two additional episodic ataxia-associated variants caused mixed gain-and loss-of function effects in ND7/23 cells and were further examined in primary murine hippocampal neuronal cultures. Neuronal firing in excitatory neurons was increased by p.Arg1629His, but decreased by p.Glu1201Lys. Neuronal firing in inhibitory neurons was decreased for both variants. No functional effect was observed for p.Arg1913Trp. In four individuals, treatment with sodium channel blockers exacerbated symptoms. Interpretation We identified episodic or chronic ataxia as new phenotypes caused by variants in SCN8A . Genotype-phenotype correlations revealed a more pronounced LOF effect for variants causing chronic ataxia. Sodium channel blockers should be avoided under these conditions. Summary for Social Media Twitter handles @cmbosselmann, @FiladelfiaGene1, @Katrine92658231, @Elegardella What is the current knowledge on the topic? Variants in SCN8A , a gene encoding the voltage-gated sodium channel NaV1.6, are associated with neurodevelopmental disorders, including epilepsy, intellectual disability, and autism spectrum disorder. What question did this study address? This study investigated whether SCN8A variants can cause predominant episodic or chronic ataxia, as well as the cellular and molecular mechanisms underlying these variants. What does this study add to our knowledge? Episodic or chronic ataxia as a sole or predominant symptom caused by NaV1.6 channel loss-of-function comprise new phenotypes in the broad spectrum associated with SCN8A dysfunction. Genotype-phenotype correlations help to differentiate between chronic and episodic ataxia. How might this potentially impact on the practice of neurology? Loss-of-function SCN8A variants may represent an underdiagnosed etiology in hereditary ataxia. Treatment with sodium channel blockers, commonly prescribed in other types of episodic ataxia, may harm these individuals, and should be avoided.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».